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1.
Nat Commun ; 11(1): 4467, 2020 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-32948751

RESUMO

Recent studies have reported that upregulation of disulfide-bond A oxidoreductase-like protein (DsbA-L) prevented lipid-induced renal injury in diabetic nephropathy (DN). However, the role and regulation of proximal tubular DsbA-L for renal tubulointerstitial fibrosis (TIF) remains unclear. In current study, we found that a proximal tubules-specific DsbA-L knockout mouse (PT-DsbA-L-KO) attenuated UUO-induced TIF, renal cell apoptosis and inflammation. Mechanistically, the DsbA-L interacted with Hsp90 in mitochondria of BUMPT cells which activated the signaling of Smad3 and p53 to produce connective tissue growth factor (CTGF) and then resulted in accumulation of ECM of BUMPT cells and mouse kidney fibroblasts. In addition, the progression of TIF caused by UUO, ischemic/reperfusion (I/R), aristolochic acid, and repeated acute low-dose cisplatin was also alleviated in PT-DsbA-L-KO mice via the activation of Hsp90 /Smad3 and p53/CTGF axis. Finally, the above molecular changes were verified in the kidney biopsies from patients with obstructive nephropathy (Ob). Together, these results suggest that DsbA-L in proximal tubular cells promotes TIF via activation of the Hsp90 /Smad3 and p53/CTGF axis.


Assuntos
Fibrose/genética , Predisposição Genética para Doença/genética , Glutationa Transferase/genética , Glutationa Transferase/metabolismo , Nefropatias/genética , Idoso , Animais , Apoptose , Fator de Crescimento do Tecido Conjuntivo/metabolismo , Nefropatias Diabéticas , Modelos Animais de Doenças , Feminino , Fibrose/patologia , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Inflamação , Rim/lesões , Nefropatias/patologia , Túbulos Renais Proximais/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias/metabolismo , Transdução de Sinais , Proteína Smad3/metabolismo , Proteína Supressora de Tumor p53/metabolismo
2.
Gene ; 758: 144952, 2020 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-32683074

RESUMO

Diabetic nephropathy (DN) as one of the most frequent microvascular complications of diabetic patients causes chronic renal failure and end-stage renal disease. Noncoding RNAs including circular RNAs (circRNAs) and micro RNAs (miRNAs) were widely reported to play a critical role in numerous human diseases including DN. This research was designed to investigate the role of circ_0000064 in diabetic nephropathy progression. The results showed that circ_0000064 significantly promoted mesangial cells proliferation and aggravated fibrosis in DN. In the subsequent mechanism investigation, we found that circ_0000064 was involved in this process by targeting micro RNA miR-143. The inhibition of miR-143 significantly reverses the effect of circ_0000064 silencing on DN. In conclusion, we demonstrated the regulatory role of circ_0000064 in DN and clarified that circ_0000064 play a role in DN via targeting miR-143. Circ_0000064 and miR-143 also showed the potential as a biomarker for DN.


Assuntos
Nefropatias Diabéticas/genética , Fibrose/genética , Células Mesangiais/patologia , MicroRNAs/genética , RNA Circular/genética , Animais , Proliferação de Células/genética , Complicações do Diabetes/genética , Complicações do Diabetes/patologia , Diabetes Mellitus/patologia , Fibrose/patologia , Humanos , Camundongos
3.
Life Sci ; 256: 117980, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32561396

RESUMO

Diabetic cardiomyopathy (DCM) is an independent and specific cardiomyopathy, which is associated with cardiac failure in diabetic patients. Currently, the pathogenesis of DCM is a popular research topic in the investigation of cardiovascular diseases. MicroRNAs (miRNAs) have been identified as the latent therapeutic targets for DCM. However, the functions and complex mechanisms of miRNAs in DCM have not been clarified. The cardiomyocyte injury model was established using high glucose (HG) ingestion, and the DCM rat model was established using 30 mg/kg streptozotocin. MicroRNA-223 (miR-223) expression was determined using qRT-PCR; the levels of NLRP3 inflammasome, fibrosis, and apoptosis-related genes and proteins were analyzed using qRT-PCR and western blot assays. Besides the morphological changes and fibrosis of myocardial tissues were evaluated using H&E and Masson staining. We discovered that miR-223 was highly expressed in the HG-induced cardiomyocyte injury model, and miR-223 inhibitor could further relieve the myocardial fibrosis and apoptosis, and inhibit NLRP3 inflammasome of HG-induced H9c2 cells. Additionally, we found that inhibition of miR-223 had obvious positive effects on the cardiac dysfunction and reduced the elevation of blood sugar in the DCM model rats. We found that the miRNA-223 inhibitor could improve the morphological structure and the degree of fibrosis in myocardial tissues in the DCM model rats. Moreover, we verified that inhibition of miR-223 could suppress the NLRP3 inflammasome activation, and alleviate myocardial fibrosis and apoptosis of the DCM model rats. In conclusion, our results suggested that miR-223 might be an underlying therapeutic target for DCM by reducing NLRP3 inflammasome activation, fibrosis, and apoptosis.


Assuntos
Apoptose/fisiologia , Cardiomiopatias Diabéticas/metabolismo , Inflamassomos/metabolismo , MicroRNAs/biossíntese , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Animais , Linhagem Celular , Cardiomiopatias Diabéticas/patologia , Fibrose/metabolismo , Fibrose/patologia , Inflamassomos/antagonistas & inibidores , MicroRNAs/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Ratos
4.
Nat Commun ; 11(1): 2768, 2020 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-32488016

RESUMO

Fibrotic disorders are some of the most devastating and poorly treated conditions in developed nations, yet effective therapeutics are not identified for many of them. A major barrier for the identification of targets and successful clinical translation is a limited understanding of the human fibrotic microenvironment. Here, we construct a stromal cell atlas of human fibrosis at single cell resolution from patients with Dupuytren's disease, a localized fibrotic condition of the hand. A molecular taxonomy of the fibrotic milieu characterises functionally distinct stromal cell types and states, including a subset of immune regulatory ICAM1+ fibroblasts. In developing fibrosis, myofibroblasts exist along an activation continuum of phenotypically distinct populations. We also show that the tetraspanin CD82 regulates cell cycle progression and can be used as a cell surface marker of myofibroblasts. These findings have important implications for targeting core pathogenic drivers of human fibrosis.


Assuntos
Contratura de Dupuytren/imunologia , Contratura de Dupuytren/metabolismo , Fibrose/imunologia , Fibrose/metabolismo , Células Estromais/metabolismo , Actinas/metabolismo , Biomarcadores/metabolismo , Quimiocinas CXC/metabolismo , Contratura de Dupuytren/patologia , Fibrose/patologia , Humanos , Molécula 1 de Adesão Intercelular/metabolismo , Medicina Molecular , Miofibroblastos/metabolismo , Tetraspaninas/metabolismo , Microambiente Tumoral/fisiologia
5.
Nat Rev Drug Discov ; 19(7): 480-494, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32555376

RESUMO

The Hippo pathway is an evolutionarily conserved signalling pathway with key roles in organ development, epithelial homeostasis, tissue regeneration, wound healing and immune modulation. Many of these roles are mediated by the transcriptional effectors YAP and TAZ, which direct gene expression via control of the TEAD family of transcription factors. Dysregulated Hippo pathway and YAP/TAZ-TEAD activity is associated with various diseases, most notably cancer, making this pathway an attractive target for therapeutic intervention. This Review highlights the key findings from studies of Hippo pathway signalling across biological processes and diseases, and discusses new strategies and therapeutic implications of targeting this pathway.


Assuntos
Neoplasias/terapia , Proteínas Serina-Treonina Quinases/metabolismo , Medicina Regenerativa/métodos , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Proteínas de Ligação a DNA/genética , Fibrose/genética , Fibrose/patologia , Fibrose/terapia , Regulação da Expressão Gênica , Humanos , Neoplasias/genética , Neoplasias/patologia , Proteínas Nucleares/genética , Transdução de Sinais , Fatores de Transcrição/genética , Cicatrização/fisiologia
6.
Am J Physiol Renal Physiol ; 319(1): F93-F105, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32475133

RESUMO

The long noncoding RNA nuclear enriched abundant transcript 1 (NEAT1) has been reported to promote liver fibrosis progression. However, its molecular mechanism in renal fibrosis was not elucidated. In the present study, an in vitro model of renal fibrosis was established with HK-2 and HKC-8 cells treated with transforming growth factor-ß1. C57BL/6 mice were used for the in vivo model with unilateral ureteral obstruction. Our results indicated that NEAT1 and collagen type I levels were significantly upregulated, whereas miR-129 was obviously downregulated, in the progression of renal fibrosis. Meanwhile, NEAT1 knockdown or miR-129 overexpression inhibited collagen type I deposition, the epithelial-mesenchymal transition process, and the inflammation response to suppress renal fibrosis. NEAT1 directly targeted miR-129, and miR-129 directly bound to collagen type I. Downregulation of miR-129 reversed inhibition of renal fibrosis induced by NEAT1 silencing, and upregulation of collagen type I also reversed inhibition of renal fibrosis caused by miR-129 overexpression. NEAT1 knockdown alleviated renal fibrosis in mice subjected to unilateral ureteral obstruction. In conclusion, NEAT1 sponged miR-129 to modulate the epithelial-mesenchymal transition process and inflammation response of renal fibrosis by regulation of collagen type I. Our study indicates a novel role in the regulation of renal fibrosis and provides a new potential treatment target for renal fibrosis.


Assuntos
Colágeno Tipo I/metabolismo , Nefropatias/metabolismo , Rim/metabolismo , MicroRNAs/metabolismo , RNA Longo não Codificante/metabolismo , Animais , Nitrogênio da Ureia Sanguínea , Linhagem Celular , Creatinina/sangue , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Fibrose/metabolismo , Fibrose/patologia , Humanos , Rim/efeitos dos fármacos , Rim/patologia , Nefropatias/patologia , Camundongos , MicroRNAs/genética , RNA Longo não Codificante/genética , Fator de Crescimento Transformador beta1/farmacologia
7.
Am J Physiol Renal Physiol ; 319(1): F139-F148, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32538151

RESUMO

Inflammation is a major determinant for the progression of chronic kidney disease (CKD). NF-κB is a master transcription factor upregulated in CKD that promotes inflammation and regulates apoptosis and vascular remodeling. We aimed to modulate this pathway for CKD therapy in a swine model of CKD using a peptide inhibitor of the NF-κB p50 subunit (p50i) fused to a protein carrier [elastin-like polypeptide (ELP)] and equipped with a cell-penetrating peptide (SynB1). We hypothesized that intrarenal SynB1-ELP-p50i therapy would inhibit NF-κB-driven inflammation and induce renal recovery. CKD was induced in 14 pigs. After 6 wk, pigs received single intrarenal SynB1-ELP-p50i therapy (10 mg/kg) or placebo (n = 7 each). Renal hemodynamics were quantified in vivo using multidetector computed tomography before and 8 wk after treatment. Pigs were then euthanized. Ex vivo experiments were performed to quantify renal activation of NF-κB, expression of downstream mediators of NF-κB signaling, renal microvascular density, inflammation, and fibrosis. Fourteen weeks of CKD stimulated NF-κB signaling and downstream mediators (e.g., TNF-α, monocyte chemoattractant protein-1, and IL-6) accompanying loss of renal function, inflammation, fibrosis, and microvascular rarefaction versus controls. All of these were improved after SynB1-ELP-p50i therapy, accompanied by reduced circulating inflammatory cytokines as well, which were evident up to 8 wk after treatment. Current treatments for CKD are largely ineffective. Our study shows the feasibility of a new treatment to induce renal recovery by offsetting inflammation at a molecular level. It also supports the therapeutic potential of targeted inhibition of the NF-κB pathway using novel drug delivery technology in a translational model of CKD.


Assuntos
Rim/efeitos dos fármacos , NF-kappa B/antagonistas & inibidores , Insuficiência Renal Crônica/tratamento farmacológico , Animais , Modelos Animais de Doenças , Sistemas de Liberação de Medicamentos , Fibrose/tratamento farmacológico , Fibrose/metabolismo , Fibrose/patologia , Rim/metabolismo , Rim/patologia , Circulação Renal/efeitos dos fármacos , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/patologia , Transdução de Sinais/efeitos dos fármacos , Suínos
8.
Int J Legal Med ; 134(4): 1275-1284, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32500199

RESUMO

Autopsies of deceased with a confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can provide important insights into the novel disease and its course. Furthermore, autopsies are essential for the correct statistical recording of the coronavirus disease 2019 (COVID-19) deaths. In the northern German Federal State of Hamburg, all deaths of Hamburg citizens with ante- or postmortem PCR-confirmed SARS-CoV-2 infection have been autopsied since the outbreak of the pandemic in Germany. Our evaluation provides a systematic overview of the first 80 consecutive full autopsies. A proposal for the categorisation of deaths with SARS-CoV-2 infection is presented (category 1: definite COVID-19 death; category 2: probable COVID-19 death; category 3: possible COVID-19 death with an equal alternative cause of death; category 4: SARS-CoV-2 detection with cause of death not associated to COVID-19). In six cases, SARS-CoV-2 infection was diagnosed postmortem by a positive PCR test in a nasopharyngeal or lung tissue swab. In the other 74 cases, SARS-CoV-2 infection had already been known antemortem. The deceased were aged between 52 and 96 years (average 79.2 years, median 82.4 years). In the study cohort, 34 deceased were female (38%) and 46 male (62%). Overall, 38% of the deceased were overweight or obese. All deceased, except for two women, in whom no significant pre-existing conditions were found autoptically, had relevant comorbidities (in descending order of frequency): (1) diseases of the cardiovascular system, (2) lung diseases, (3) central nervous system diseases, (4) kidney diseases, and (5) diabetes mellitus. A total of 76 cases (95%) were classified as COVID-19 deaths, corresponding to categories 1-3. Four deaths (5%) were defined as non-COVID-19 deaths with virus-independent causes of death. In eight cases, pneumonia was combined with a fulminant pulmonary artery embolism. Peripheral pulmonary artery embolisms were found in nine other cases. Overall, deep vein thrombosis has been found in 40% of the cases. This study provides the largest overview of autopsies of SARS-CoV-2-infected patients presented so far.


Assuntos
Betacoronavirus , Infecções por Coronavirus/mortalidade , Infecções por Coronavirus/patologia , Pulmão/patologia , Pneumonia Viral/mortalidade , Pneumonia Viral/patologia , Distribuição por Idade , Idoso , Idoso de 80 Anos ou mais , Células Epiteliais Alveolares/patologia , Autopsia , Betacoronavirus/genética , Betacoronavirus/isolamento & purificação , Comorbidade , Infecção Hospitalar/mortalidade , Exsudatos e Transudatos , Feminino , Fibroblastos/patologia , Fibrose/patologia , Alemanha/epidemiologia , Células Gigantes/patologia , Humanos , Masculino , Megacariócitos/patologia , Pessoa de Meia-Idade , Casas de Saúde/estatística & dados numéricos , Tamanho do Órgão , Sobrepeso/epidemiologia , Pandemias , Reação em Cadeia da Polimerase , Embolia Pulmonar/patologia , Instituições Residenciais/estatística & dados numéricos , Distribuição por Sexo , Doença Relacionada a Viagens , Trombose Venosa/patologia
9.
Int J Legal Med ; 134(4): 1285-1290, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32504146

RESUMO

Forensic investigations generally contain extensive morphological examinations to accurately diagnose the cause of death. Thus, the appearance of a new disease often creates emerging challenges in morphological examinations due to the lack of available data from autopsy- or biopsy-based research. Since late December 2019, an outbreak of a novel seventh coronavirus disease has been reported in China caused by "severe acute respiratory syndrome coronavirus 2" (SARS-CoV-2). On March 11, 2020, the new clinical condition COVID-19 (Corona-Virus-Disease-19) was declared a pandemic by the World Health Organization (WHO). Patients with COVID-19 mainly have a mild disease course, but severe disease onset might result in death due to proceeded lung injury with massive alveolar damage and progressive respiratory failure. However, the detailed mechanisms that cause organ injury still remain unclear. We investigated the morphological findings of a COVID-19 patient who died during self-isolation. Pathologic examination revealed massive bilateral alveolar damage, indicating early-phase "acute respiratory distress syndrome" (ARDS). This case emphasizes the possibility of a rapid severe disease onset in previously mild clinical condition and highlights the necessity of a complete autopsy to gain a better understanding of the pathophysiological changes in SARS-CoV-2 infections.


Assuntos
Betacoronavirus , Infecções por Coronavirus/patologia , Pulmão/patologia , Pneumonia Viral/patologia , Células Epiteliais Alveolares/patologia , Autopsia , Tosse/virologia , Diabetes Mellitus Tipo 2 , Febre/virologia , Fibrina/metabolismo , Fibrose/patologia , Humanos , Hiperplasia/patologia , Hipertensão , Pulmão/metabolismo , Linfócitos/patologia , Macrófagos/patologia , Masculino , Megacariócitos/patologia , Metaplasia/patologia , Pessoa de Meia-Idade , Neutrófilos/patologia , Pandemias , Quarentena , Taquicardia/virologia , Trombose/patologia
11.
Life Sci ; 254: 117797, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32417371

RESUMO

AIMS: Atrial remodeling, including structural and electrical remodeling, is considered as the substrate in the development of atrial fibrillation (AF). Structural remodeling mainly involves atrial fibrosis, and electrical remodeling is closely related to the changes of ion channels in atrial myocytes. In this study, we aimed to investigate the changes of ion channels in atrial remodeling induced by CIH in rats, which provide the explication for the mechanisms of AF. MATERIALS AND METHODS: 80 male Sprague-Dawley rats were randomized into two groups: Control and CIH group (n = 40). CIH rats were subjected to CIH 8 h/d for 30 days. Atrial epicardial conduction velocity, conduction inhomogeneity and AF inducibility were examined. Masson's trichrome staining was used to evaluate the extent of atrial fibrosis, and the expression levels of ion channel subunits were measured by RT-qPCR, Western blot, and IHC, respectively. The remaining 40 rats were used for whole-cell patch clamp experiments. Action potential, INa, ICa-L, Ito were recorded and compared between two groups. KEY FINDINGS: CIH rats showed increased AF inducibility, atrial interstitial collagen deposition, APD, expression levels of RyR2, p-RyR2, CaMKII, p-CaMKII, and decreased atrial epicardial conduction velocity, expression levels of Nav1.5, Cav1.2, Kv1.5, Kv4.2, Kv4.3 compared to the Control rats, and the current density of INa, ICa-L, Ito were significantly decreased in CIH group. SIGNIFICANCE: We observed significant atrial remodeling induced by CIH in our rat model, which was characterized by changes in ion channels. These changes may be the mechanisms of CIH promoting AF.


Assuntos
Remodelamento Atrial/fisiologia , Hipóxia/fisiopatologia , Canais Iônicos/fisiologia , Potenciais de Ação/fisiologia , Animais , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/biossíntese , Doença Crônica , Fibrose/complicações , Fibrose/patologia , Átrios do Coração/metabolismo , Átrios do Coração/patologia , Átrios do Coração/fisiopatologia , Hipóxia/complicações , Hipóxia/metabolismo , Canais Iônicos/biossíntese , Masculino , Potenciais da Membrana/fisiologia , Ratos , Canal de Liberação de Cálcio do Receptor de Rianodina/biossíntese
12.
Mol Carcinog ; 59(7): 754-765, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32363633

RESUMO

Fibroblasts are a key component of the tumor microenvironment (TME) that can serve as a scaffold for tumor cell migration and augment the tumor's ability to withstand harsh conditions. When activated by external or endogenous stimuli, normal fibroblasts become cancer associated fibroblasts (CAFs), a heterogeneous group of stromal cells in the tumor that are phenotypically and epigenetically different from normal fibroblasts. Dynamic crosstalk between cancer cells, immune cells, and CAFs through chemokines and surface signaling makes the TME conducive to tumor growth. When activated, CAFs promote tumorigenesis and metastasis through several phenomena including regulation of tumor immunity, metabolic reprogramming of the TME, extracellular matrix remodeling and contraction, and induction of therapeutic resistance. Ionizing radiation (radiation theraphy [RT]) is a potent immunological stimulant that has been shown to increase cytotoxic Teff infiltration and IFN-I stimulated genes. RT, however, is unable to overcome the infiltration and activation of immunosuppressive cells which can contribute to tumor progression. Another paradox of RT is that, while very effective at killing cancer cells, it can contribute to the formation of CAFs. This review examines how the interplay between CAFs and immune cells during RT contributes to organ fibrosis, immunosuppression, and tumor growth. We focus on targeting mechanistic pathways of CAF formation as a potentially effective strategy not only for preventing organ fibrosis, but also in hampering tumor progression in response to RT.


Assuntos
Fibroblastos Associados a Câncer/imunologia , Fibroblastos Associados a Câncer/patologia , Neoplasias/imunologia , Neoplasias/patologia , Animais , Fibroblastos Associados a Câncer/efeitos da radiação , Fibrose/imunologia , Fibrose/patologia , Humanos , Neoplasias/radioterapia , Radioterapia/métodos , Microambiente Tumoral/imunologia , Microambiente Tumoral/efeitos da radiação
13.
Am J Physiol Cell Physiol ; 319(2): C277-C287, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32432932

RESUMO

Severe burn injury induces a myriad of deleterious effects to skeletal muscle, resulting in impaired function and delayed recovery. Following burn, catabolic signaling and myofiber atrophy are key fiber-intrinsic determinants of weakness; less well understood are alterations in the interstitial environment surrounding myofibers. Muscle quality, specifically alterations in the extracellular matrix (ECM), modulates force transmission and strength. We sought to determine the impact of severe thermal injury on adaptation to the muscle ECM and quantify muscle fibrotic burden. After a 30% total body surface area dorsal burn, spinotrapezius muscle was harvested from mice at 7 (7d, n = 5), 14 (14d, n = 4), and 21 days (21d, n = 4), and a sham control group was also examined (Sham, n = 4). Expression of transforming growth factor-ß (TGFß), myostatin, and downstream effectors and proteases involved in fibrosis and collagen remodeling were measured by immunoblotting, and immunohistochemical and biochemical analyses assessed fibrogenic cell abundance and collagen deposition. Myostatin signaling increased progressively through 21 days postburn alongside fibrogenic/adipogenic progenitor cell expansion, with abundance peaking at 14 days postburn. Postburn, elevated expression of tissue inhibitor of matrix metalloproteinase 1 supported collagen remodeling resulting in a net accumulation of muscle collagen content. Collagen accumulation peaked at 14 days postburn but remained elevated through 21 days postburn, demonstrating minimal resolution of burn-induced fibrosis. These findings highlight a progressive upregulation of fibrogenic processes following burn injury, eliciting a fibrotic muscle phenotype that hinders regenerative capacity and is not resolved with 21 days of recovery.


Assuntos
Queimaduras/genética , Fibrose/genética , Músculo Esquelético/metabolismo , Miostatina/genética , Fator de Crescimento Transformador beta/genética , Animais , Queimaduras/metabolismo , Queimaduras/patologia , Proliferação de Células/genética , Colágeno/genética , Matriz Extracelular/genética , Matriz Extracelular/metabolismo , Fibroblastos/metabolismo , Fibroblastos/patologia , Fibrose/metabolismo , Fibrose/patologia , Regulação da Expressão Gênica/genética , Humanos , Camundongos , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares Esqueléticas/patologia , Músculo Esquelético/lesões , Músculo Esquelético/patologia , Transdução de Sinais/genética
14.
Gastroenterol. hepatol. (Ed. impr.) ; 43(4): 179-187, abr. 2020. ilus, graf, tab
Artigo em Inglês | IBECS | ID: ibc-190794

RESUMO

INTRODUCTION: A proper quantification of the inflammatory activity in Crohn's disease (CD) lesions is needed to establish the appropriate management for each patient. The aim of this study is to evaluate the inflammatory activity of affected segments in small bowel lesions using dynamic studies of magnetic resonance enterography (MRE) in patients undergoing surgery, and their correlation with the level of inflammation and histological fibrosis of the surgical piece. METHODS: A prospective, consecutive, observational, clinical study was conducted that included all the patients with small bowel CD that underwent surgery in this center between March 2011 and September 2013. Diagnosis was established according to Lennard-Jones criteria and the Montreal classification. All the patients underwent MRE within three months before surgery, using a routine protocol involving Liver Acquisition with Volume Acceleration-Extended Volume (LAVA-XV) sequence for the dynamic studies before intravenous administering of gadolinium and 30, 70, 120, and 420s after administering this. The results allowed the designing of graphics with different uptake patterns. The Chiorean classification was used in the histological analysis, as well as a modified version published previously by this study group. RESULTS: A total of 28 patients with 47 lesions were analyzed. There was a significant correlation between both curve patterns, including the modified Chiorean classification (p < 0.0001) as well as the level of inflammation (p < 0.0001) and fibrosis (p < 0.002). Inflammatory patterns of dynamic studies are related to histological findings with 80.9% accuracy (sensitivity=75.7%; specificity=100%). CONCLUSION: There is a high correlation between dynamic enhancement studies and the level of inflammatory activity. MRE is a suitable tool to differentiate between inflammatory and fibrotic lesions, making it useful to decide the appropriate management of each patient


INTRODUCCIÓN: Se necesita una cuantificación adecuada de la actividad inflamatoria en las lesiones de la enfermedad de Crohn (EC) para establecer el tratamiento adecuado para cada paciente. El objetivo de este estudio es evaluar la actividad inflamatoria de los segmentos afectados en las lesiones del intestino delgado mediante estudios dinámicos de enterografía por resonancia magnética (ERM). MÉTODOS: Estudio prospectivo, consecutivo, observacional y clínico, que incluye a todos los pacientes con EC del intestino delgado que se sometieron a cirugía en nuestro centro entre marzo de 2011 y septiembre de 2013. El diagnóstico se estableció de acuerdo con los criterios de Lennard-Jones y la clasificación de Montreal. Todos los pacientes se sometieron a una ERM dentro de los 3 meses previos a la cirugía, aplicando el protocolo de rutina y secuencias preestablecidas. Para el estudio dinámico se empleó la secuencia Adquisición hepática con aceleración de volumen-Volumen extendido (LAVA-XV), antes de la administración intravenosa (IV) de gadolinio, y 30, 70, 120 y 420s después de esta administración. Los resultados permiten diseñar gráficos con diferentes patrones de captación. En el análisis histológico se utilizó la clasificación de Chiorean, así como una versión modificada creada por nuestro grupo de estudio. RESULTADOS: En total se analizaron 28 pacientes con 47 lesiones. Se detectó una correlación significativa entre ambos patrones de curva, incluyendo la clasificación de Chiorean modificada (p < 0,0001), así como el grado inflamatorio (p < 0,0001) y de fibrosis (p < 0,002). Los patrones inflamatorios de los estudios dinámicos se relacionaron con los hallazgos histológicos con una precisión del 80,9% (S=75,7%; E=100%). CONCLUSIÓN: Existe una alta correlación entre los estudios dinámicos y el grado de actividad inflamatoria. La ERM constituye una herramienta adecuada para diferenciar entre lesiones inflamatorias y fibróticas, siendo útil para colaborar en la decisión terapéutica


Assuntos
Humanos , Adolescente , Adulto Jovem , Adulto , Doença de Crohn/diagnóstico por imagem , Imagem por Ressonância Magnética/métodos , Intestino Delgado/diagnóstico por imagem , Doença de Crohn/patologia , Intestino Delgado/patologia , Estudos Prospectivos , Gadolínio/administração & dosagem , Fibrose/diagnóstico por imagem , Fibrose/patologia , Doença de Crohn/cirurgia , Inflamação/diagnóstico por imagem , Inflamação/patologia
15.
Adv Exp Med Biol ; 1229: 181-195, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32285412

RESUMO

Diabetic cardiomyopathy (DCM) is the leading cause of morbidity and mortality in diabetic population worldwide, characteristic by cardiomyocyte hypertrophy, apoptosis and myocardial interstitial fibrosis and eventually developing into heart failure. Non-coding RNAs, such as microRNAs (miRNAs), circular RNAs (circRNAs), long non-coding RNAs (lncRNAs) and other RNAs without the protein encoding function were emerging as a popular regulator in various types of processes during human diseases. The evidences have shown that miRNAs are regulators in diabetic cardiomyopathy, such as insulin resistance, cardiomyocytes apoptosis, and inflammatory, especially their protective effect on heart function. Besides that, the functions of lncRNAs and circRNAs have been gradually confirmed in recent years, and their functions in DCM have become increasingly prominent. We highlighted the nonnegligible roles of non-coding RNAs in the pathological process of DCM and showed the future possibilities of these non-coding RNAs in DCM treatment. In this chapter, we summarized the present advance of the researches in this filed and raised the concern and the prospect in the future.


Assuntos
Cardiomiopatias Diabéticas , RNA não Traduzido , Cardiomiopatias Diabéticas/genética , Cardiomiopatias Diabéticas/patologia , Fibrose/genética , Fibrose/patologia , Humanos , MicroRNAs , Miocárdio/patologia , RNA Circular , RNA Longo não Codificante
16.
Adv Exp Med Biol ; 1221: 669-684, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32274731

RESUMO

Organ fibrosis is defined as a deregulated wound-healing process characterized by a progressive accumulation of fibrous tissue and by reduced remodeling that can lead to the loss of functionality of the affected organ. This pathological process is quite common in several parenchymal organs such as kidneys, liver, and lungs and represents a real health emergency in developed western countries since a real anti-fibrotic therapy is not yet available in most cases. Heparanase (HPSE), which is the enzyme that cuts off the side chains of heparan sulfate (HS) proteoglycan, appears to be involved in the aetiopathogenesis of fibrosis in all these organs, even if with different mechanisms. Here we discuss how the interplay between HPSE and components of the immune and inflammatory responses can activate recruitment, proliferation, and activation of myofibroblasts which represent the main cell type responsible for the deposition of fibrous matrix. Finally, bearing in mind that once the activity of HPSE is inhibited no other molecule is able to perform the same function, it is desirable that this enzyme could prove to be a suitable pharmacological target in anti-fibrotic therapy.


Assuntos
Fibrose/enzimologia , Fibrose/patologia , Glucuronidase/metabolismo , Fibrose/metabolismo , Proteoglicanas de Heparan Sulfato , Humanos , Miofibroblastos , Especificidade de Órgãos , Cicatrização
17.
Presse Med ; 49(1): 104014, 2020 Apr.
Artigo em Francês | MEDLINE | ID: mdl-32234381

RESUMO

IgG4-related disease (IgG4-RD) has been accepted as a distinct entity in various fields. It is being increasingly diagnosed and treated in routine practice. However, difficulties are still associated with the diagnostic process. Serum IgG4 elevations and imaging studies are useful, but not entirely diagnostic for this condition. Therefore, a pathological examination still plays an important role. Three characteristic microscopic changes are dense lymphoplasmacytic infiltration, storiform fibrosis, and obliterative phlebitis. IgG4 immunostaining reveals many IgG4-positive plasma cells and an IgG4/IgG-positive cell ratio of more than 40%. In addition to the number and ratio of IgG4-positive plasma cells, the diffuse distribution of positive plasma cells needs to be confirmed because IgG4-positive plasma cells may focally aggregate in many other conditions. In small biopsy samples, it is important to recognize not only characteristic findings, but also microscopic changes that are unlikely to occur in IgG4-RD because the identification of the latter findings leads to the exclusion of this condition. Another challenging field regards the diagnosis of long-standing disease. Along with disease progression, inflammatory infiltrate decreases, while storiform fibrosis and obliterative phlebitis are suspected to persistently exist. Therefore, the recognition of the latter two findings will be a diagnostic clue. Given the general suspicion that IgG4-RD has recently been over-diagnosed, precise tissue examinations based on the proposed standards and close clinicopathological correlations are crucial.


Assuntos
Doença Relacionada a Imunoglobulina G4/patologia , Imunoglobulina G/análise , Plasmócitos/patologia , Linfócitos B/patologia , Biópsia , Hiperplasia do Linfonodo Gigante/diagnóstico , Hiperplasia do Linfonodo Gigante/patologia , Diagnóstico Diferencial , Fibrose/diagnóstico , Fibrose/patologia , Histiocitose Sinusal/diagnóstico , Histiocitose Sinusal/patologia , Humanos , Imunoglobulina G/sangue , Doença Relacionada a Imunoglobulina G4/diagnóstico , Imuno-Histoquímica , Flebite/diagnóstico , Flebite/patologia , Plasmócitos/imunologia , Linfócitos T/patologia
18.
Invest Ophthalmol Vis Sci ; 61(4): 15, 2020 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-32298438

RESUMO

Purpose: Pathological neovascularization and fibrosis are common pathological changes of many retinal diseases, such as proliferative retinopathy (PR) and age-related macular degeneration (AMD). Treatment modalities for these pathological changes are limited. The purpose of the present study was to test the effects of palmitoylethanolamide (PEA), an endocannabinoid mimetic amide, on retinal neovascularization and fibrosis and to determine its molecular mechanism of action. Methods: A rat Müller cell line (rMC-1), a mouse model of oxygen-induced retinopathy (OIR), and the very-low-density lipoprotein receptor (VLDLR) knockout mouse model were used. PEA was intraperitoneally injected or orally administrated in animal models. Inflammation and profibrotic changes were evaluated by western blot analysis. Glial fibrillary acidic protein (GFAP) and peroxisome proliferator-activated receptor alpha (PPARα) were measured by RT-PCR and western blot analysis. Results: Profibrotic changes were present in OIR and Vldlr-/- retinas. PEA significantly alleviated inflammation and inhibited neovascularization in OIR and Vldlr-/- retinas and suppressed profibrotic changes in OIR and Vldlr-/- retinas. Moreover, PEA potently suppressed Müller gliosis in these retinas. In rMC-1 cells, PEA suppressed Müller gliosis, reduced inflammatory cytokines, and attenuated profibrotic changes. Further, both mRNA and protein levels of PPARα were elevated in the retina under PEA treatment, and the effects of PEA were abolished in Pparα-/- OIR mice. Conclusions: PEA reduced retinal neovascularization and fibrotic changes and suppressed Müller gliosis in experimental PR and neovascular AMD by activating PPARα. PEA may be a potential treatment for retinopathies with pathological neovascularization and fibrosis.


Assuntos
Agonistas de Receptores de Canabinoides/uso terapêutico , Etanolaminas/uso terapêutico , Gliose/tratamento farmacológico , PPAR alfa/metabolismo , Ácidos Palmíticos/uso terapêutico , Retina/patologia , Neovascularização Retiniana/tratamento farmacológico , Administração Oral , Animais , Western Blotting , Linhagem Celular , Modelos Animais de Doenças , Células Ependimogliais/efeitos dos fármacos , Fibrose/tratamento farmacológico , Fibrose/metabolismo , Fibrose/patologia , Proteína Glial Fibrilar Ácida/genética , Proteína Glial Fibrilar Ácida/metabolismo , Gliose/metabolismo , Gliose/patologia , Marcação In Situ das Extremidades Cortadas , Injeções Intraperitoneais , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Oxigênio/toxicidade , PPAR alfa/genética , Ratos , Reação em Cadeia da Polimerase em Tempo Real , Receptores de LDL/genética , Retina/metabolismo , Neovascularização Retiniana/induzido quimicamente , Neovascularização Retiniana/metabolismo , Neovascularização Retiniana/patologia
19.
Autoimmun Rev ; 19(5): 102515, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32173517

RESUMO

Systemic sclerosis (SSc) is an autoimmune disease which is characterized by vasculopathy, tissue fibrosis and activation of the innate and adaptive immune system. Clinical features of the disease consists of skin thickening and internal organ involvement. Due to the heterogeneous nature of the disease it is difficult to predict disease progression and complications. Despite the discovery of novel autoantibodies associated with SSc, there is an unmet need for biomarkers for diagnosis, disease progression and response to treatment. To date, the use of single (surrogate) biomarkers for these purposes has been unsuccessful. Combining multiple biomarkers in to predictive panels or ultimately algorithms could be more precise. Given the limited therapeutic options and poor prognosis of many SSc patients, a better understanding of the immune-pathofysiological profiles might aid to an adjusted therapeutic approach. Therefore, we set out to explore immunological fingerprints in various clinically defined forms of SSc. We used multilayer profiling to identify unique immune profiles underlying distinct autoantibody signatures. These immune profiles could fill the unmet need for prognosis and response to therapy in SSc. Here, we present 3 pathophysiological fingerprints in SSc based on the expression of circulating antibodies, vascular markers and immunomodulatory mediators.


Assuntos
Medicina de Precisão , Escleroderma Sistêmico/diagnóstico , Escleroderma Sistêmico/fisiopatologia , Autoanticorpos/imunologia , Biomarcadores/análise , Feminino , Fibrose/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Escleroderma Sistêmico/imunologia , Escleroderma Sistêmico/patologia
20.
PLoS One ; 15(3): e0229870, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32160231

RESUMO

BACKGROUND AND AIM: To evaluate the effect of intermittent pringle maneuver (IPM) on the long-term prognosis and recurrence of hepatocellular carcinoma (HCC). METHODS: Eligible studies were identified by PubMed and other databases from Jan 1st 1990 to Mar 31st 2019. Hazard ratios (HR) with 95% confidence interval (CI) were calculated to evaluate the effects of IPM on the long-term prognosis and recurrence of patients with HCC. RESULTS: Six studies were enrolled in this meta-analysis. Results showed that there were no differences between IPM group and non-IPM group in the pooled HRs for the overall survival (OS) and disease-free survival (DFS) (HR 1.04, 95%CI 0.84~1.28, P = 0.74; HR 0.93, 95%CI 0.81~1.07, P = 0.29; respectively). However, subgroup analysis showed that the pooled Odd ratios (OR) for the 1-year OS and DFS rates of the IPM group when compared with the non-IPM group were 0.65 (95% CI 0.45~0.94, P = 0.02), 0.38 (95% CI 0.20~0.72, P = 0.003), respectively. In addition, there were no significant differences in the proportions of liver cirrhosis, HBsAg (+), Child-Pugh A class, multiple tumor, vascular invasion, and major hepatectomy between groups of IPM and non-IPM. CONCLUSION: Since IPM would increase the risk of early-recurrence, it should be used cautiously in the procedure of hepatectomy for resectable HCC. However, the current conclusion needs further validation. TRIAL REGISTRY NUMBER: CRD 42019124923.


Assuntos
Carcinoma Hepatocelular/cirurgia , Fibrose/cirurgia , Hepatectomia/métodos , Neoplasias Hepáticas/cirurgia , Carcinoma Hepatocelular/epidemiologia , Carcinoma Hepatocelular/patologia , Ensaios Clínicos como Assunto , Intervalo Livre de Doença , Feminino , Fibrose/epidemiologia , Fibrose/patologia , Humanos , Neoplasias Hepáticas/epidemiologia , Neoplasias Hepáticas/patologia , Masculino , Recidiva Local de Neoplasia , Prognóstico
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